Autoimmunity. Autoimmune Disease

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1 Autoimmunity Reactivity to self antigens: T cells B cells Autoimmune Disease Autoreactivity: Leading to tissue damage or dysfunction Occurring in the absence of ongoing infection 1

2 SLE Pathogenesis Immune activation Target organ injury Epidemiology Prevalence: 17-48/100,000 worldwide but as high as 207/100,000 in an Afro- Caribbean population in England Female:Male ratio is approximately 9:1 post-puberty and pre-menopausal Ethnic Variance: More common in Black (3x), Hispanic (2-3x) and Asian 2x) populations 2

3 ACR Criteria for Diagnosis 1. Malar Rash: fixed erythema, flat or raised, over the malar eminences, sparing the nasolabial folds 2. Discoid Rash: Erythematous raised patches with adherent keratotic scaling and follicular plugging: scarring may occur 3. Photosensitivity: Reaction to sunlight, resulting in the development of or increase in skin rash 4. Oral Ulcers: Oral or nasopharyngial ulceration, usually painless 5. Arthritis: Nonerosive arthritis involving two or more peripheral joints 6. Serositis: Pleuritis or pericarditis 7. Renal Disorder: proteinuria greater than.5 gm/day and/or cellular casts 8. Neurologic Disorder: Seizures and/or psychosis in the absence of drugs or metabolic disturbances which are known to cause such effects 9. Hematologic Disorder: Hemolytic anemia, leukopenia (< 4000), lymphopenia (<1500) or thrombocytopenia (<100,000) 10. ANA: Positive test for antinuclear antibodies in the absence of drugs known to induce it. 11. Immunologic Disorder: Elevated serum antibody titers to dsdna or Sm, a positive LE cell prep or a false positive serologic test for syphilis Signs and Symptoms Symptoms Occurrence (ever) Arthralgias 95% Fever more than 100 degrees F (38 degrees C) 90% Arthritis 80% Prolonged or extreme fatigue 81% Skin Rashes 74% Anemia 71% Kidney Involvement 50% Pleurisy 45% Sun or light sensitivity (photosensitivity) 30% Hair loss 27% Abnormal blood clotting problems 20% Raynaud's phenomenon 17% Seizures 15% Mouth or nose ulcers 12% 3

4 Anti-nuclear antibody patterns Homogeneous Rim Speckled GENES RISK BEHAVIOR ENVIRONMENT Smoking Sun exposure Antigen Hormones 4

5 Genes Implicated in Murine SLE MHC Apoptotic pathways Cytokines:costimulatory Signalling molecules Clearance of cellular debris Regulatory pathways Genes Implicated in Human SLE HLA Signaling: PTPN22 and CD22 Apoptosis: BCL-2 Cytokines: IL-10 Regulatory mechanisms:ctla4, PD-1 and FcRIIb Clearance of apoptotic debris: complement, DNAse, activating FcRs 5

6 Genes Triggers Apoptotic debris Infection UV light Silica Etiology Silica may be a surrogate for endotoxin Clearance of Apoptotic Cells Natural autoantibodies: DNA, PS, phospholipid Y YY TLR 3 TLR 7 TLR 9 macrophage dendritic cell 6

7 Interferon Signature Infection Bacterial EBV Somatic Mutation, Affinity Maturation and the Generation of Autoreactivity Germinal Center 7

8 UV Light Malar Rash Lupus Band Test Hormonal Regulation Estrogen-increases Bcl-2, decreases BCR signal Deleted BCR signal No E2 With E2 Survives Antigen concentration 8

9 Disease Progression Nucleic acid-antibody complexes Y Y Y CD40L CD40 IL-12 IFN-α BAFF TNFα IL-10 APC CD4 peptide MHC II TCR B7 CD28 Activated T H IL-2 IFNγ Anti-DNA/RNP B cell Y Disease Progression Regulatory cells Inhibitory Pathways Regulatory T cell Production of IL-10 or TGF-β Contact-dependent mechanisms Functionally Unresponsive T cell Y B cell Activation Y Y FcR II B cell Inhibition 9

10 Pathogenicity of anti-dsdna Antibodies B. Hahn, NEJM 1998 Target Organ Vulnerability Kidney Cellular infiltration Sclerosis 10

11 Tissue Damage Mechanisms - cytotoxic cells - cytokines - antibodies Critical Considerations 1) Mechanism of autoreactivity may differ from mechanism of organ damage. 2) What exacerbates autoimmunity may ameliorate tissue damage ie. Low TNF 11

12 Late Sequelae Heart-accelerated atherosclerosis Brain-cognitive impairment Therapy Immunosuppression:current Global Immunosuppression: novel 1) Immunoablation: B cell ablation 2) Costimulatory blockade 3) Cytokine blockade 4) Induction of immune deviation 5) Induction of regulatory cells Antigen-specific Therapy:fantasy 1) vaccines, 2) toxic conjugates 3) tolerance induction 12

13 Stringency of lymphocyte selection and predisposition to autoimmunity Protective repertoire Leakiness in Negative Selection Negative selection Therapeutic Strategy Treat during remission: Increase stringency of negative selection 13

14 Vasculitis A systemic process in which blood vessel architecture is destroyed by inflammatory cells. Vasculitis-induced injury may lead to increased vascular permeability, vessel weakening and aneurism formation, intimal proliferation and thrombosis resulting in obstruction and tissue ischemia. Vasculitis Heterogenous group of disorders All share a propensity for angiocentric inflammation and necrosis Represent a remarkably diverse range of clinical symptoms, severities and outcomes 14

15 Primary Vasculitis/Classification Large Vessel Vasculitis Takayasus Arteritis Giant Cell Arteritis Medium-Sized Vessel Vasculitis Polyarteritis Nodosa Kawasaki s Primary CNS Angiitis Small Vessel Vasculitis ANCA+ Wegener s Granulomatosis Churg Strauss Microscopic Polyarteritis ANCA- Henoch Schonlein Purpura Cryoglobulinemia Behcet s Hypersensitivity vasculitis ANCA+ Vasculitides Wegener s granulomatosis (WG), Churg Strauss (CS) and Microscopic Polyarteritis (MPA) All involve medium to small vessels Peak age onset 55 Male:female ratio is approximately 2:1 15

16 ANCA/Pathophysiology canca targets proteinase3; very specific for Wegener s (99%) isolated reports in amoebiasis, lymphoma and SLE panca Targets myeloperoxidase; associated with Churg-Strauss reported commonly in RA, autoimmune hepatitis, ulcerative colitis with different antigen targets (lactoferrin, elastase, cathepsin G) ANCA/Pathogenicity? Mouse myeloperoxidase-anca induce vasculitis in Rag2 mice ANCA binding to neutrophils or monocytes in vitro induces a respiratory burst, degranulation and release of proinflammotory molecules resulting in tissue damage ANCA binding to proteinase3 on activated endothelial cells induces cell injury and death Increased surface expression of PR3 on PMNs correlates with disease activity 16